Studies were performed to elucidate the association of HLA antigens with disease conditions. Antisera, detecting specific HLA-DR determinants, were used in immunoprecipitation studies to define molecular characteristics of the antigen-bearing proteins and in in vitro immune response studies in order to determine the effect of these sera on cellular interactions. HLA-A, B, C, DR, MT and MB antigen frequencies were found to be restricted in Pima Indians. There were differences in HLA antigen frequencies in patients with psoriatic arthritis depending on the degree of psoriasis or arthritis. HLA alloantigen frequenceis were determined in families with multiple cases of two different diseases, the variant form of 21-hydroxylase deficiency and systemic lupus erythematosus. Linkage of the 21-hydroxylase deficiency syndrome to HLA genes is not unlike that seen for the congenital disease, suggesting more than a one-gene defect in this disease. In families with multiple cases of systemic lupus erythematosus, common HLA haplotypes were seen more frequently than in diseased individuals. Takayasu's arteritis, a frequent disease in Japan and rare in the U.S., was found to be associated with the MT3 antigen which has a higher frequency in Japanese than in the North American Caucasians. Immuno-precipitation studies with HLA-DR alloantisera demonstrated that some antigenic determinants are on the alpha chain of the HLA-DR dimer and others on beta chains. The studies also suggest that there are at least three HLA-DR genes. Alloantisera directed against the HLA-DR determinants activate suppressor cells in in vitro immune response studies, demonstrating an immunoregulatory function of these molecules. The first definitive demonstration of HLA-associated immune response genes was documented in studies of in vitro insulin response in diabetic patients.